{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T23:44:05Z","timestamp":1789343045034,"version":"build-2803163510"},"reference-count":42,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,4]],"date-time":"2026-01-04T00:00:00Z","timestamp":1767484800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Technology and National Science and Technology Council, Taiwan","award":["MOST 110-2314-B-303-008"],"award-info":[{"award-number":["MOST 110-2314-B-303-008"]}]},{"name":"Ministry of Science and Technology and National Science and Technology Council, Taiwan","award":["NSTC 113-2314-B-303-009-MY3"],"award-info":[{"award-number":["NSTC 113-2314-B-303-009-MY3"]}]},{"name":"Hualien Tzu Chi Hospital and Tzu Chi Medical Foundation","award":["TCRD111-041"],"award-info":[{"award-number":["TCRD111-041"]}]},{"name":"Hualien Tzu Chi Hospital and Tzu Chi Medical Foundation","award":["TCRD113-071"],"award-info":[{"award-number":["TCRD113-071"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>High-grade serous ovarian carcinoma (HGSC) is predominantly diagnosed at advanced stages with extensive peritoneal metastasis. A pivotal early event in HGSC development is the peritoneal seeding of tumor cells originating from the fallopian tube epithelial (FTE) precursor lesions. Ovulation releases follicular fluid (FF), which is known to contain oncogenic factors that promote FTE cell transformation. However, the specific mechanisms and factors within FF that drive the early metastatic seeding of precancerous FTE cells remain poorly defined. We investigated the role of FF in the peritoneal dissemination of FTE-derived cells, and the abundance of fibronectin (FN) as a potential key mediator. Functional assays were performed using FN-depleted FF to assess its impact on migration, invasion, anchorage-independent growth, and peritoneal attachment. The role of the fibronectin receptor, integrin \u03b21 (ITGB1), and the signaling pathways were evaluated via knockdown studies. In vivo xenograft models were used to quantify peritoneal seeding, and mechanistic studies elucidated the involved signaling pathways. We identified FN as a critical component of FF, present at high concentrations (~210 \u00b5g\/mL), that potently drives FTE cell migration, invasion, and peritoneal seeding. Depletion of FN from FF abrogated the majority of these pro-metastatic activities in vitro and led to a dramatic 82% reduction in peritoneal tumor seeding in vivo. Knockdown of ITGB1 similarly impaired seeding. Mechanistically, FF-derived FN activates the ITGB1\/FAK-SRC signaling pathway to promote tumor cell motility and colonization. Our study establishes FF-fibronectin as an important regulator of the early peritoneal seeding of HGSC precursor cells. These findings reveal a direct link between ovulation and HGSC development, suggesting that targeting the FN-ITGB1 signaling axis may offer a novel preventive strategy for high-risk individuals.<\/jats:p>","DOI":"10.3390\/cells15010080","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T15:28:57Z","timestamp":1767626937000},"page":"80","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Ovulation-Derived Fibronectin Promotes Peritoneal Seeding of High-Grade Serous Carcinoma Precursor Cells via Integrin \u03b21 Signaling"],"prefix":"10.3390","volume":"15","author":[{"given":"Che-Fang","family":"Hsu","sequence":"first","affiliation":[{"name":"Center for Prevention and Therapy of Gynecological Cancers, Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang-Yuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Prevention and Therapy of Gynecological Cancers, Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan"},{"name":"Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 970, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vaishnavi","family":"Seenan","sequence":"additional","affiliation":[{"name":"Center for Prevention and Therapy of Gynecological Cancers, Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan"},{"name":"Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan"},{"name":"Department of Biotechnology, Vel Tech High Tech Dr. Rangarajan Dr. Sakunthala Engineering College, Chennai 600062, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pao-Chu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics & Gynecology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2717-2681","authenticated-orcid":false,"given":"Tang-Yuan","family":"Chu","sequence":"additional","affiliation":[{"name":"Center for Prevention and Therapy of Gynecological Cancers, Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan"},{"name":"Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 970, Taiwan"},{"name":"Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan"},{"name":"Department of Obstetrics & Gynecology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"E359","DOI":"10.1002\/ijc.29210","article-title":"Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012","volume":"136","author":"Ferlay","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/s41571-024-00881-3","article-title":"Global epidemiology of epithelial ovarian cancer","volume":"21","author":"Webb","year":"2024","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_3","first-page":"183","article-title":"Recent progress in the diagnosis and treatment of ovarian cancer","volume":"61","author":"Jelovac","year":"2011","journal-title":"CA Cancer J. Clin."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1016\/j.hoc.2018.07.010","article-title":"Diagnosis and Treatment of Ovarian Cancer","volume":"32","author":"Orr","year":"2018","journal-title":"Hematol. Oncol. Clin. N. Am."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1097\/PAS.0b013e3181cf3d79","article-title":"The origin and pathogenesis of epithelial ovarian cancer: A proposed unifying theory","volume":"34","author":"Kurman","year":"2010","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.ajpath.2020.09.006","article-title":"The Origin of Ovarian Cancer Species and Precancerous Landscape","volume":"191","author":"Shih","year":"2021","journal-title":"Am. J. Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"x16","DOI":"10.1093\/annonc\/mdt463","article-title":"Origin and molecular pathogenesis of ovarian high-grade serous carcinoma","volume":"24","author":"Kurman","year":"2013","journal-title":"Ann. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1038\/s41467-017-00962-1","article-title":"High grade serous ovarian carcinomas originate in the fallopian tube","volume":"8","author":"Papp","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Kim, J., Park, E.Y., Kim, O., Schilder, J.M., Coffey, D.M., Cho, C.H., and Bast, R.C. (2018). Cell Origins of High-Grade Serous Ovarian Cancer. Cancers, 10.","DOI":"10.3390\/cancers10110433"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Soong, T.R., Kolin, D.L., Teschan, N.J., and Crum, C.P. (2018). Back to the Future? The Fallopian Tube, Precursor Escape and a Dualistic Model of High-Grade Serous Carcinogenesis. Cancers, 10.","DOI":"10.20944\/preprints201810.0416.v1"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/j.ygyno.2018.11.033","article-title":"The fallopian tube, \u201cprecursor escape\u201d and narrowing the knowledge gap to the origins of high-grade serous carcinoma","volume":"152","author":"Soong","year":"2019","journal-title":"Gynecol. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1097\/PAS.0b013e318282da7f","article-title":"Fallopian tube intraluminal tumor spread from noninvasive precursor lesions: A novel metastatic route in early pelvic carcinogenesis","volume":"37","author":"Bijron","year":"2013","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1002\/path.5145","article-title":"Evidence for lineage continuity between early serous proliferations (ESPs) in the Fallopian tube and disseminated high-grade serous carcinomas","volume":"246","author":"Soong","year":"2018","journal-title":"J. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Hsu, C.F., Chen, P.C., Seenan, V., Ding, D.C., and Chu, T.Y. (2021). Ovulatory Follicular Fluid Facilitates the Full Transformation Process for the Development of High-Grade Serous Carcinoma. Cancers, 13.","DOI":"10.3390\/cancers13030468"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1186\/s12935-024-03406-1","article-title":"Human peritoneal fluid exerts ovulation- and nonovulation-sourced oncogenic activities on transforming fallopian tube epithelial cells","volume":"24","author":"Hsu","year":"2024","journal-title":"Cancer Cell Int."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/j.ebiom.2019.01.061","article-title":"IGF-axis confers transformation and regeneration of fallopian tube fimbria epithelium upon ovulation","volume":"41","author":"Hsu","year":"2019","journal-title":"EBioMedicine"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1016\/j.neo.2021.09.006","article-title":"Ovulation sources coagulation protease cascade and hepatocyte growth factor to support physiological growth and malignant transformation","volume":"23","author":"Huang","year":"2021","journal-title":"Neoplasia"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1186\/s12935-024-03614-9","article-title":"Epidermal growth factor receptor ligands enriched in follicular fluid exosomes promote oncogenesis of fallopian tube epithelial cells","volume":"24","author":"Khine","year":"2024","journal-title":"Cancer Cell Int."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Hsu, C.F., Seenan, V., Wang, L.Y., and Chu, T.Y. (2022). Ovulation Enhances Intraperitoneal and Ovarian Seedings of High-Grade Serous Carcinoma Cells Originating from the Fallopian Tube: Confirmation in a Bursa-Free Mouse Xenograft Model. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23116211"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s12014-015-9077-6","article-title":"Proteomic analysis of human follicular fluid from fertile women","volume":"12","author":"Zamah","year":"2015","journal-title":"Clin. Proteom."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Dalton, C.J., and Lemmon, C.A. (2021). Fibronectin: Molecular Structure, Fibrillar Structure and Mechanochemical Signaling. Cells, 10.","DOI":"10.20944\/preprints202108.0010.v1"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s12964-023-01338-3","article-title":"Integrinbeta-1 in disorders and cancers: Molecular mechanisms and therapeutic targets","volume":"22","author":"Su","year":"2024","journal-title":"Cell Commun. Signal."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Lin, T.C., Yang, C.H., Cheng, L.H., Chang, W.T., Lin, Y.R., and Cheng, H.C. (2019). Fibronectin in Cancer: Friend or Foe. Cells, 9.","DOI":"10.3390\/cells9010027"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"674","DOI":"10.7150\/jca.16901","article-title":"Fibronectin: How Its Aberrant Expression in Tumors May Improve Therapeutic Targeting","volume":"8","author":"Wang","year":"2017","journal-title":"J. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Ranga, V., Dakal, T.C., Maurya, P.K., Johnson, M.S., Sharma, N.K., and Kumar, A. (2025). Role of RGD-binding Integrins in ovarian cancer progression, metastasis and response to therapy. Integr. Biol., 17.","DOI":"10.1093\/intbio\/zyaf003"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.ygyno.2015.08.010","article-title":"Hepatocyte growth factor secreted by ovarian cancer cells stimulates peritoneal implantation via the mesothelial-mesenchymal transition of the peritoneum","volume":"139","author":"Nakamura","year":"2015","journal-title":"Gynecol. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"215779","DOI":"10.1016\/j.canlet.2022.215779","article-title":"Versican secreted by the ovary links ovulation and migration in fallopian tube derived serous cancer","volume":"543","author":"Russo","year":"2022","journal-title":"Cancer Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e27336","DOI":"10.1016\/j.heliyon.2024.e27336","article-title":"Follicular fluid aids cell adhesion, spreading in an age independent manner and shows an age-dependent effect on DNA damage in fallopian tube epithelial cells","volume":"10","author":"Salvi","year":"2024","journal-title":"Heliyon"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1016\/j.fertnstert.2005.11.058","article-title":"Follicular fluid levels of inhibin A, inhibin B, and activin A levels reflect changes in follicle size but are not independent markers of the oocyte\u2019s ability to fertilize","volume":"85","author":"Wen","year":"2006","journal-title":"Fertil. Steril."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"C343","DOI":"10.1152\/ajpcell.00048.2003","article-title":"VCAM-1-mediated Rac signaling controls endothelial cell-cell contacts and leukocyte transmigration","volume":"285","author":"Mul","year":"2003","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"13329","DOI":"10.2147\/OTT.S273803","article-title":"The Roles of Integrin alpha5beta1 in Human Cancer","volume":"13","author":"Hou","year":"2020","journal-title":"Onco Targets Ther."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Su, Y., Iacob, R.E., Li, J., Engen, J.R., and Springer, T.A. (2022). Dynamics of integrin alpha5beta1, fibronectin, and their complex reveal sites of interaction and conformational change. J. Biol. Chem., 298.","DOI":"10.1016\/j.jbc.2022.102323"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1002\/(SICI)1097-0215(19991112)83:4<476::AID-IJC7>3.0.CO;2-V","article-title":"Hepatocyte growth factor (HGF) in ovarian epithelial tumour fluids stimulates the migration of ovarian carcinoma cells","volume":"83","author":"Sowter","year":"1999","journal-title":"Int. J. Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1038\/onc.2010.532","article-title":"Ligand-independent activation of c-Met by fibronectin and alpha(5)beta(1)-integrin regulates ovarian cancer invasion and metastasis","volume":"30","author":"Mitra","year":"2011","journal-title":"Oncogene"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/S0959-437X(00)00155-6","article-title":"Coordinate signaling by integrins and receptor tyrosine kinases in the regulation of G1 phase cell-cycle progression","volume":"11","author":"Assoian","year":"2001","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"311","DOI":"10.5483\/BMBRep.2010.43.5.311","article-title":"Crosstalk between integrin and receptor tyrosine kinase signaling in breast carcinoma progression","volume":"43","author":"Soung","year":"2010","journal-title":"BMB Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1186\/s12967-023-04696-1","article-title":"The characteristics and the multiple functions of integrin beta1 in human cancers","volume":"21","author":"Sun","year":"2023","journal-title":"J. Transl. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.ccell.2019.01.007","article-title":"Integrin Signaling in Cancer: Mechanotransduction, Stemness, Epithelial Plasticity, and Therapeutic Resistance","volume":"35","author":"Cooper","year":"2019","journal-title":"Cancer Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1007\/s11373-005-9061-7","article-title":"Crosstalk between hepatocyte growth factor and integrin signaling pathways","volume":"13","author":"Chan","year":"2006","journal-title":"J. Biomed. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Stanislovas, J., and Kermorgant, S. (2022). c-Met-integrin cooperation: Mechanisms, tumorigenic effects, and therapeutic relevance. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.994528"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"E8685","DOI":"10.1073\/pnas.1701821114","article-title":"Cross-activating c-Met\/beta1 integrin complex drives metastasis and invasive resistance in cancer","volume":"114","author":"Jahangiri","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e138928","DOI":"10.1172\/jci.insight.138928","article-title":"Role of c-Met\/beta1 integrin complex in the metastatic cascade in breast cancer","volume":"6","author":"Lau","year":"2021","journal-title":"JCI Insight"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/1\/80\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T13:59:40Z","timestamp":1774274380000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/1\/80"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,4]]},"references-count":42,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["cells15010080"],"URL":"https:\/\/doi.org\/10.3390\/cells15010080","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,4]]}}}